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Downloaded from Bioscientifica.Com at 10/03/2021 12:22:59PM Via Free Access 61 1 Journal of Molecular S Iyer and S K Agarwal Epigenetic regulation in 61:1 R13–R24 Endocrinology endocrine cells REVIEW Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types Sucharitha Iyer and Sunita K Agarwal Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA Correspondence should be addressed to S K Agarwal: [email protected] Abstract Epigenetic regulation is emerging as a key feature in the molecular characteristics of Key Words various human diseases. Epigenetic aberrations can occur from mutations in genes f neuroendocrine associated with epigenetic regulation, improper deposition, removal or reading of f pancreas histone modifications, DNA methylation/demethylation and impaired non-coding f parathyroid RNA interactions in chromatin. Menin, the protein product of the gene causative for f pituitary the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin- associated protein complexes and also regulates some non-coding RNAs, thus participating in epigenetic control mechanisms. Germline inactivating mutations in the MEN1 gene that encodes menin predispose patients to develop endocrine tumors of the parathyroids, anterior pituitary and the duodenopancreatic neuroendocrine tissues. Therefore, functional loss of menin in the various MEN1-associated endocrine cell types can result in epigenetic changes that promote tumorigenesis. Because epigenetic changes are reversible, they can be targeted to develop therapeutics for restoring the tumor epigenome to the normal state. Irrespective of whether epigenetic alterations are the cause or consequence of the tumorigenesis process, targeting the endocrine tumor- associated epigenome offers opportunities for exploring therapeutic options. This review presents epigenetic control mechanisms relevant to the interactions and targets of menin, and the contribution of epigenetics in the tumorigenesis of endocrine cell types Journal of Molecular from menin loss. Endocrinology (2018) 61, R13–R24 Introduction Epigenetic changes observed in various human diseases regulation in tumor etiology is highlighted by the have been shown to play important roles as disease discovery of mutations in genes encoding factors that drivers, biomarkers and therapeutic targets. Epigenetic participate in epigenetic regulatory mechanisms in changes can occur due to mutations in factors that various cancers (Koschmann et al. 2017). Menin, the control epigenetic modifications or in response to protein encoded by the gene responsible for causing the metabolic or environmental signals, which lead to multiple endocrine neoplasia type 1 (MEN1) syndrome, improper deposition, removal or reading of histone participates in epigenetic regulation (Shilatifard 2012, van modifications, DNA methylation/demethylation and Nuland et al. 2013). Patients with the MEN1 syndrome impaired non-coding RNA interactions in chromatin carry germline heterozygous inactivating mutations (Allis et al. 2015). The evidence for the role of epigenetic in the MEN1 gene located at chromosome 11q13, that http://jme.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/JME-18-0050 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/03/2021 12:22:59PM via free access -18-0050 Journal of Molecular S Iyer and S K Agarwal Epigenetic regulation in 61:1 R14 Endocrinology endocrine cells encodes menin, which predisposes to the development of could potentially promote tumorigenesis. Furthermore, tumors in multiple endocrine organs (Chandrasekharappa evidence from genome and exome sequencing efforts et al. 1997, Lemmens et al. 1997). The main MEN1- of sporadic non-functioning and functioning PNETs, associated endocrine cell types that form tumors are parathyroid adenoma and lung neuroendocrine tumors located in the parathyroids, anterior pituitary and the have shown additional somatic mutations in other genes duodenopancreatic neuroendocrine tissues (Thakker associated with epigenetic control mechanisms that et al. 2012). Other MEN1-associated endocrine tumors predict epigenetic changes to promote tumorigenesis in include foregut carcinoids that arise from neuroendocrine these endocrine cell types (Jiao et al. 2011, Cromer et al. cells of the lung, thymus or gastrointestinal (GI) tract. 2012, Chou et al. 2016, Romano et al. 2017, Scarpa et al. The tumors are classified as functioning when they 2017, Simbolo et al. 2017, Wang et al. 2017). hypersecrete the hormones characteristic of the endocrine Menin is a 67 kDa ubiquitously expressed cell types affected, or non-functioning when they do predominantly nuclear protein, with no intrinsic not hypersecrete any hormones. Parathyroid tumors enzymatic activity. As stated earlier, menin is a tumor are functioning causing primary hyperparathyroidism suppressor in the context of MEN1-associated endocrine due to excessive parathyroid hormone (PTH) secretion. cell types; however, menin has been shown to act as a pro- Pituitary and duodenopancreatic neuroendocrine tumors oncogenic co-factor in mixed lineage leukemia (Yokoyama in MEN1 patients are observed to be either functioning et al. 2005, Muntean & Hess 2012). The crystal structure (prolactinoma, 20%; somatotropinoma, 10%; gastrinoma, of menin shows a deep pocket that can act as a binding 40%; insulinoma, 10%) or non-functioning (pituitary, site for interacting proteins (Protein Data Bank No. 3RE2 5%; PNETs, 20–55%) (Schussheim et al. 2001, Thakker and 3U84) (Murai et al. 2011, Huang et al. 2012). Evidence et al. 2012, Marini et al. 2017). In the context of these from protein–protein interaction studies have shown endocrine tumors, MEN1 acts as a classic tumor suppressor that menin is involved in epigenetic regulation and gene because human MEN1-associated tumors show loss gene transcription through interaction with proteins in of heterozygosity (LOH) at 11q13 resulting in biallelic chromatin-associated protein complexes and transcription loss/inactivation of MEN1 (Chandrasekharappa et al. factors, affecting the expression of target genes such as 1997, Lemmens et al. 1997). Similarly, in genetically genes that control cell proliferation (Karnik et al. 2005, Wu engineered mouse models, germline targeted deletion of & Hua 2011). Interacting partners of menin also include both copies of the Men1 gene causes embryonic lethality, proteins that participate in cell adhesion, cell division, while germline targeted deletion of one copy of the cell motility, cell signaling, cytoskeletal structure, DNA Men1 gene generates live mice that later in life develop repair in response to DNA damage and studies conducted endocrine tumors similar to those seen in the human in Drosophila melanogaster have shown a role of menin MEN1 syndrome with LOH at the Men1 locus (Agarwal in the maintenance of genomic stability (Busygina et al. 2014, Agarwal 2017b). 2004, Hendy et al. 2009, Agarwal 2017a, Feng et al. 2017a). Interestingly, somatic MEN1 mutations are also Investigations to elucidate the biological function of detected in 30–40% of sporadic tumors of MEN1- menin through protein–protein interaction studies have associated endocrine cell types – parathyroid adenomas, significantly advanced our knowledge about the potential gastrinomas, pancreatic neuroendocrine tumors (PNETs) roles of menin in various cellular pathways, but they have and lung neuroendocrine tumors (Zhuang et al. 1997, been mainly conducted using cell lines (HEK293, HeLa, Debelenko et al. 1997, Jiao et al. 2011, Cromer et al. 2012, HepG2, K562 and mouse embryo fibroblasts (MEFs)) that Newey et al. 2012, Scarpa et al. 2017, Simbolo et al. 2017). are unrelated to MEN1-associated endocrine cell types. Among sporadic PNETs, MEN1 mutations are detected in Follow-up functional characterization of some interactions the non-functioning PNETs, but rarely in the functioning of menin have been performed in endocrine/endocrine- PNETs (insulinomas) (Jiao et al. 2011, Cao et al. 2013, related cell lines (βlox5, BON1, INS-1, MIN6, NIH-H720, Lichtenauer et al. 2015, Chou et al. 2016, Scarpa et al. NIH-727, and QGP1) albeit not in endocrine cell lines 2017, Wang et al. 2017). Also, MEN1 mutations are rarely with MEN1 mutations or that lack menin because no such detected in sporadic pituitary tumors (Poncin et al. 1999, cell lines are currently available. The focus of this review Newey et al. 2013, Bi et al. 2017, Marques & Korbonits will be on studies conducted using endocrine/endocrine- 2017). Because menin participates in epigenetic regulation, related cell lines or menin-null endocrine tumors from functional loss of menin in the various MEN1-associated mouse models. This review excludes the discussion of endocrine cell types would lead to epigenetic changes that menin’s interaction with transcription factors because http://jme.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/JME-18-0050 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/03/2021 12:22:59PM via free access Journal of Molecular S Iyer and S K Agarwal Epigenetic regulation in 61:1 R15 Endocrinology endocrine cells they were recently well covered elsewhere (Agarwal (Zoghbi & Beaudet 2016). Technological advances in 2017a, Dreijerink et al. 2017, Feng et al. 2017a). In this chromatin immunoprecipitation and next-generation review, we present a survey of the published literature to sequencing
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